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GBP1与PIM1相互作用的首个抑制剂的鉴定。对开发一类针对紫杉醇耐药癌细胞的新型抗癌药物的意义。

Identification of the first inhibitor of the GBP1:PIM1 interaction. Implications for the development of a new class of anticancer agents against paclitaxel resistant cancer cells.

作者信息

Andreoli Mirko, Persico Marco, Kumar Ajay, Orteca Nausicaa, Kumar Vineet, Pepe Antonella, Mahalingam Sakkarapalayam, Alegria Antonio E, Petrella Lella, Sevciunaite Laima, Camperchioli Alessia, Mariani Marisa, Di Dato Antonio, Novellino Ettore, Scambia Giovanni, Malhotra Sanjay V, Ferlini Cristiano, Fattorusso Caterina

机构信息

Danbury Hospital Research Institute , 24 Hospital Avenue, Danbury, Connecticut 06810, United States.

出版信息

J Med Chem. 2014 Oct 9;57(19):7916-32. doi: 10.1021/jm5009902. Epub 2014 Sep 26.

DOI:10.1021/jm5009902
PMID:25211704
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4191604/
Abstract

Class III β-tubulin plays a prominent role in the development of drug resistance to paclitaxel by allowing the incorporation of the GBP1 GTPase into microtubules. Once in the cytoskeleton, GBP1 binds to prosurvival kinases such as PIM1 and initiates a signaling pathway that induces resistance to paclitaxel. Therefore, the inhibition of the GBP1:PIM1 interaction could potentially revert resistance to paclitaxel. A panel of 44 4-azapodophyllotoxin derivatives was screened in the NCI-60 cell panel. The result is that 31 are active and the comparative analysis demonstrated specific activity in paclitaxel-resistant cells. Using surface plasmon resonance, we were able to prove that NSC756093 is a potent in vitro inhibitor of the GBP1:PIM1 interaction and that this property is maintained in vivo in ovarian cancer cells resistant to paclitaxel. Through bioinformatics, molecular modeling, and mutagenesis studies, we identified the putative NSC756093 binding site at the interface between the helical and the LG domain of GBP1. According to our results by binding to this site, the NSC756093 compound is able to stabilize a conformation of GBP1 not suitable for binding to PIM1.

摘要

III类β-微管蛋白通过允许GBP1 GTP酶掺入微管，在对紫杉醇的耐药性发展中起重要作用。一旦进入细胞骨架，GBP1就会与诸如PIM1等促生存激酶结合，并启动一条诱导对紫杉醇耐药的信号通路。因此，抑制GBP1:PIM1相互作用可能会逆转对紫杉醇的耐药性。在NCI-60细胞系中筛选了一组44种4-氮杂鬼臼毒素衍生物。结果是31种具有活性，并且比较分析表明在耐紫杉醇细胞中具有特异性活性。利用表面等离子体共振，我们能够证明NSC756093是GBP1:PIM1相互作用的一种有效的体外抑制剂，并且这种特性在耐紫杉醇的卵巢癌细胞体内也得以维持。通过生物信息学、分子建模和诱变研究，我们在GBP1的螺旋结构域和LG结构域之间的界面处确定了推定的NSC756093结合位点。根据我们通过结合该位点得到的结果，NSC756093化合物能够稳定GBP1的一种不适合与PIM1结合的构象。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b8d0/4191604/60e40b65df98/jm-2014-009902_0012.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b8d0/4191604/7d6a762f308e/jm-2014-009902_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b8d0/4191604/b897fcfc39d7/jm-2014-009902_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b8d0/4191604/dbb32281a5ad/jm-2014-009902_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b8d0/4191604/423a6272e9a4/jm-2014-009902_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b8d0/4191604/93f9f0e8447e/jm-2014-009902_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b8d0/4191604/53ccc362566b/jm-2014-009902_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b8d0/4191604/60e40b65df98/jm-2014-009902_0012.jpg

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